Association between blood markers and the progression of osseointegration in percutaneous prostheses patients-A pilot study.

Patients implanted with osseointegrated (OI) prosthetic systems have reported vastly improved upper and lower extremity prosthetic function compared with their previous experience with socket-suspension systems. However, OI systems have been associated with superficial and deep-bone infections and implant loosening due, in part, to a failure of the osseointegration process. Although monitoring the osseointegration using circulating biomarkers has clinical relevance for understanding the progression of osseointegration with these devices, it has yet to be established.

Sintered fluorapatite scaffolds as an autograft-like engineered bone graft.

Hydroxyapatite (HA)-based materials are widely used as bone substitutes due to their inherent biocompatibility, osteoconductivity, and bio-absorption properties. However, HA scaffolds lack compressive strength when compared to autograft bone. It has been shown that the fluoridated form of HA, fluorapatite (FA), can be sintered to obtain this desired strength as well as slower degradation properties.

Phage and Antibiotic Combinations Reduce in Static and Dynamic Biofilms Grown on an Implant Material.

causes the majority of implant-related infections. These infections present as biofilms, in which bacteria adhere to the surface of foreign materials and form robust communities that are resilient to the human immune system and antibiotic drugs. The heavy use of broad-spectrum antibiotics against these pathogens disturbs the host's microbiome and contributes to the growing problem of antibiotic-resistant infections.

Mutual Cooperativity of Three Allosteric Sites on the Dopamine D1 Receptor.

An amine-containing molecule called Compound A has been reported by a group from Bristol-Myers Squibb to act as a positive allosteric modulator (PAM) at the dopamine D1 receptor. We synthesized the more active enantiomer of Compound A (BMS-A1) and compared it with the D1 PAMs DETQ and MLS6585, which are known to bind to intracellular loop 2 and the extracellular portion of transmembrane helix 7, respectively. Results from D1/D5 chimeras indicated that PAM activity of BMS-A1 tracked with the presence of D1 sequence in the N-terminal/extracellular region of the D1 receptor, a unique location compared with either of the other PAMs.

Ensemble Docking Approach to Mitigate Pregnane X Receptor-Mediated CYP3A4 Induction Risk.

Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity.

A preliminary, observational study using whole-blood RNA sequencing reveals differential expression of inflammatory and bone markers post-implantation of percutaneous osseointegrated prostheses.

Aims: While the benefits of direct skeletal attachment of artificial limbs are well recognized, device failure due to infection and insufficient osseointegration remain obstacles to obtaining consistently successful outcomes. Currently, the potential for device failure is assessed by subjective pain, clinical function scores, radiographic evidence of bone atrophy, and the presence of radiolucent lines at the bone-implant interface, and subjective pain and function scores. Our hypothesis is that measurable biological indices might add another objective means to assess trends toward bone and stomal healing.

A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk.

The human pregnane X receptor (hPXR) regulates the expression of major drug metabolizing enzymes. A wide range of drug candidates bind and activate hPXR, and hence are at risk of increasing drug-drug interactions and reducing clinical efficacy. hPXR structural features that function as hot spots for ligand binding are identified and highlighted in this concise review.

Fluorapatite and fluorohydroxyapatite apatite surfaces drive adipose-derived stem cells to an osteogenic lineage.

Purpose: Hydroxyapatite (HA) scaffolds are common replacement materials used in the clinical management of critical-sized bone defects. This study was undertaken to examine the potential benefits of fluoridated derivatives of hydroxyapatite, fluorapatite (FA), and fluorohydroxyapatite (FHA) as bone scaffolds in conjunction with adipose-derived stem cells (ADSCs). If FHA and FA surfaces could drive the differentiation of stem cells to an osteogenic phenotype, the combination of these ceramic scaffolds with ADSCs could produce materials with mechanical strength and remodeling potential comparable to autologous bone.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity.

[Transcutaneous Osseointegrated Prosthetic Systems (TOPS) for Transfemoral Amputees - A Six-Year Retrospective Analysis of the Latest Prosthetic Design in Germany].

Purpose: A retrospective analysis of clinical outcomes and complication rates of patients treated with the latest implant design of the so-called Endo-Exo-Femoral Prosthesis (EEFP) was performed. The aim is to gain specific information on long-term complications of this treatment-method.

Methods: In January 2019, data of all transfemoral amputees who were treated with TOPS at an acute clinic in Schleswig-Holstein from 2010 to 2016 were retrospectively analysed.

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials.

Variation in bone response to the placement of percutaneous osseointegrated endoprostheses: A 24-month follow-up in sheep.

Percutaneous osseointegrated (OI) devices for amputees are metallic endoprostheses, that are surgically implanted into the residual stump bone and protrude through the skin, allowing attachment of an exoprosthetic limb. In contrast to standard socket suspension systems, these percutaneous OI devices provide superior attachment platforms for artificial limbs. However, bone adaptation, which includes atrophy and/or hypertrophy along the extent of the host bone-endoprosthetic interface, is seen clinically and depends upon where along the bone the device ultimately transfers loading forces to the skeletal system.

Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1,3)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 () as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation.

Analysis of the Stomal Microbiota of a Percutaneous Osseointegrated Prosthesis: A Longitudinal Prospective Cohort Study.

Percutaneous osseointegrated (OI) prostheses (POPs) are used to skeletally attach artificial limbs in amputees. While any permanent percutaneous interface is at risk of becoming infected by the resident microbiota colonizing the stoma, most of these patients remain infection-free. Avoidance of infection likely depends upon a mechanically and/or biologically stable skin-to-implant interface.

Epidermal growth factor receptor genes are overexpressed within the periprosthetic soft-tissue around percutaneous devices: A pilot study.

Epidermal downgrowth around percutaneous devices produce sinus tracts, which then accumulate bacteria becoming foci of infection. This mode to failure is epidermal-centric, and is accelerated by changes in the chemokines and cytokines of the underlying periprosthetic granulation tissue (GT). In order to more fully comprehend the mechanism of downgrowth, in this 28-day study, percutaneous devices were placed in 10 Zucker diabetic fatty rats; 5 animals were induced with diabetes mellitus II (DM II) prior to the surgery and 5 animals served as a healthy, nondiabetic cohort.

Characterization and evaluation of fluoridated apatites for the development of infection-free percutaneous devices.

The wound healing process in the soft tissues adjacent to percutaneous implants induces "epithelial downgrowth", and subsequently, a sinus tract around the device. This provides an optimal environment for bacterial colonization and proliferation. In an attempt to arrest downgrowth and achieve epithelial attachment to a device surface, we have sought to mimic the most common and successful percutaneous organ, the tooth.

Intracellular Binding Site for a Positive Allosteric Modulator of the Dopamine D1 Receptor.

The binding site for DETQ [2-(2,6-dichlorophenyl)-1-((1,3)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1)-yl)ethan-1-one], a positive allosteric modulator (PAM) of the dopamine D1 receptor, was identified and compared with the binding site for CID 2886111 [-(6--butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide], a reference D1 PAM. From D1/D5 chimeras, the site responsible for potentiation by DETQ of the increase in cAMP in response to dopamine was narrowed down to the N-terminal intracellular quadrant of the receptor; arginine-130 in intracellular loop 2 (IC2) was then identified as a critical amino acid based on a human/rat species difference. Confirming the importance of IC2, a 2-adrenergic receptor construct in which the IC2 region was replaced with its D1 counterpart gained the ability to respond to DETQ.

Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders.

DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine.

A 24-month evaluation of a percutaneous osseointegrated limb-skin interface in an ovine amputation model.

Percutaneous osseointegrated (OI) prostheses directly connect an artificial limb to the residual appendicular skeleton via a permanently implanted endoprosthesis with a bridging connector that protrudes through the skin. The resulting stoma produces unique medical and biological challenges. Previously, a study using a large animal amputation model indicated that infection could be largely prevented, for at least a 12-month period, but the terminal epithelium continued to downgrow.

An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis.

Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a K of 26 nM.

Fifteen years of experience with Integral-Leg-Prosthesis: Cohort study of artificial limb attachment system.

Integral-Leg-Prosthesis (ILP) is a comparatively new attachment system that allows direct skeletal docking of artificial limbs. Between January 1999 and December 2013, 69 patients with transfemoral amputation were fitted with ILPs by a single German surgeon. Device design iterations and surgical techniques evolved during these years.

Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.

The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core.

Radiographic evaluation of bone adaptation adjacent to percutaneous osseointegrated prostheses in a sheep model.

Background: Percutaneous osseointegrated prostheses (POPs) are being investigated as an alternative to conventional socket suspension and require a radiographic followup in translational studies to confirm that design objectives are being met.

Questions/purposes: In this 12-month animal study, we determined (1) radiographic signs of osseointegration and (2) radiographic signs of periprosthetic bone hypertrophy and resorption (adaptation) and (3) confirmed them with the histologic evidence of host bone osseointegration and adaptation around a novel, distally porous-coated titanium POP with a collar.

Methods: A POP device was designed to fit the right metacarpal bone of sheep.

Pig dorsum model for examining impaired wound healing at the skin-implant interface of percutaneous devices.

Percutaneous medical devices are indispensable in contemporary clinical practice, but the associated incidence of low to moderate mortality infections represents a significant economic and personal cost to patients and healthcare providers. Percutaneous osseointegrated prosthetics also suffer from a similar risk of infection, limiting their clinical acceptance and usage in patients with limb loss. We hypothesized that transepidermal water loss (TEWL) management at the skin-implant interface may improve and maintain a stable skin-to-implant interface.